title: miR-25 and miR-92a regulate insulin I biosynthesis in rats.
abstract: The 3' UTR of insulin has been identified as a critical region that confers mRNA stability, which is crucial for promoting transcription in response to glucose challenge. miRNAs are endogenously encoded non-coding RNAs that function as regulators of gene expression. This regulatory function is generally mediated by complementary binding to the 3'UTR of its mRNA targets that affects subsequent translational process. Genes involved in the regulation of glucose homeostasis, particularly in insulin production, have been found as targets of several miRNAs. Yet, no direct miRNA-based regulators of insulin biosynthesis have been identified. In this study, identification of possible miRNA-based regulators of insulin production is explored. Members of a miRNA family, miR-25 and miR-92a, are found as direct modulators of insulin expression. Overexpression of miR-25 or miR-92a reduced insulin expression while inhibition of miR-25 and miR-92a expression using corresponding antagomiRs promoted insulin expression and ultimately enhanced glucose-induced insulin secretion. Furthermore, suppression of insulin secretion by pre miR-9 could be attenuated by treatment with anti-miR-25 or miR-92a. Interestingly, we found the binding site of miR-25 and miR-92a to overlap with that of PTBP1, an important RNA binding molecule that stabilizes insulin mRNA for translation. Despite the increase in PTBP1 protein in the pancreas of diabetic rats, we observed insulin expression to be reduced alongside upregulation of miR-25 and miR-92a, suggesting an intricate regulation of insulin (bio)synthesis at its mRNA level.
authors.affiliation: Department of Biochemistry; Yong Loo Lin School of Medicine; National University Health System; Singapore.
authors.forename: Dwi
authors.initials: D
authors.lastname: Setyowati Karolina
authors.forename: Sugunavathi
authors.initials: S
authors.lastname: Sepramaniam
authors.forename: Hui Zhing
authors.initials: HZ
authors.lastname: Tan
authors.forename: Arunmozhiarasi
authors.initials: A
authors.lastname: Armugam
authors.forename: Kandiah
authors.initials: K
authors.lastname: Jeyaseelan
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010179:Pancreas / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012689:Sequence Homology, Nucleic Acid
chemical_list: D020413:3' Untranslated Regions; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007328:Insulin; D035683:MicroRNAs; C475523:Ptbp1 protein, rat; D012333:RNA, Messenger; D038941:Polypyrimidine Tract-Binding Protein
keywords: 3′ untranslated region; gene regulation; hyperglycemia; insulin biosynthesis; microRNAs